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Apparent diffusion coefficient as a non-invasive predictor of treatment response and recurrence in locally advanced rectal cancer
Clinical Radiology 68 (2013) e524ee531
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Apparent diffusion coefficient as a non-invasive predictor of treatment response and recurrence in locally advanced rectal cancer A. Elmi*, S.S. Hedgire, D. Covarrubias, S.M. Abtahi, P.F. Hahn, M. Harisinghani Division of Abdominal Imaging and Interventional Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
article in formation Article history: Received 29 January 2013 Received in revised form 8 May 2013 Accepted 15 May 2013
AIM: To evaluate the role of pretreatment apparent diffusion coefficient (ADC) as a predictor of treatment response and local recurrence in patients with locally advanced rectal cancer who underwent neoadjuvant therapy. MATERIALS AND METHODS: Forty-nine patients who underwent preoperative diffusionweighted magnetic resonance imaging (MRI) followed by neoadjuvant chemoradiation and surgery were enrolled in the study. The mean tumour ADC was measured independently from multiple, non-overlapping regions of interest (ROIs) to cover the entire tumour area on a single section by two radiologists and patients were followed postoperatively for a median of 16.4 months. Diagnostic accuracy of ADC for predicting treatment response and recurrence was evaluated using the area under the receiver-operating characteristic (ROC) curve, sensitivity, specificity, and predictive values. Univariate and multivariate analyses including clinical tumour (cT) staging, carcinoembryonic antigen (CEA) level, lymph-node involvement, tumour grade, surgical margin, vascular involvement, and ADC were performed with respect to recurrence. Interobserver agreement of ADC values was assessed. RESULTS: Twenty patients showed response to neoadjuvant therapy and recurrence was noted in 17 patients. Low pretreatment ADC, MRI findings of cT4 staging, and node involvement were significantly related to poor treatment response. Sensitivity and specificity of ADC ¼ 0.833 103 mm2/s for prediction of treatment response was 75 and 48% for reader 1 and 65 and 52% for reader 2, respectively. Univariate and multivariate analyses identified pretreatment tumour ADC as the only predictive factor for recurrence. Sensitivity and specificity of ADC ¼ 0.833 103 mm2/s for prediction of recurrence was 86 and 77% for reader 1 and 80 and 69% for reader 2, respectively. Interobserver agreement for measuring ADC was good with a kappa value of 0.70. CONCLUSION: Pretreatment rectal tumour ADC values may be an early biomarker for predicting treatment response and local recurrence in patients who underwent neoadjuvant chemoradiation. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction * Guarantor and correspondent: A. Elmi, Massachusetts General Hospital, Division of Abdominal Imaging and Interventional Radiology, 55 Fruit St, White 270, Boston, MA 02114, USA. Tel.: þ1 617 726 8380. E-mail address: [email protected] (A. Elmi).
Neoadjuvant chemoradiotherapy (NACR) followed by surgery has been established as the standard-of-care for locally advanced rectal cancer.1 There is significant individual variation in the response to NACR.2,3 Patients who
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achieve a pathological complete response have shown increased disease-free survival.4 Moreover, local recurrence after surgery remains a significant problem in patients with rectal cancer with reported incidence of 30e50%.5,6 Early detection is one of the cornerstones of successful management of local recurrence in rectal cancer; however, in the early phase, recurring tumour is often obscured on imaging by concomitant inflammation and scarring caused by chemoradiation and surgery.7 Therefore, it is important to identify prognostic factors in order to decide whether or not NACR is a favourable treatment modality and ideally to identify patients at high risk of disease recurrence who may benefit from intense neoadjuvant treatment protocols.8,9 Various preoperative and postoperative variables have been used to predict the degree of treatment response and recurrence after NACR but with questionable accuracy.10,11 The inclusion of biomarkers and/or imaging tools that mirror the behaviour of rectal cancer may potentially improve such predictive accuracy. Few studies have evaluated magnetic resonance imaging (MRI) for predicting the response to NACR in rectal cancer. Recently, anatomical MRI along with diffusion-weighted (DW) MRI has emerged as preoperative staging methods for rectal tumours. DW MRI, a component of functional MRI, is able to assess biological characteristics such as tissue cellularity and water content. This provides tissue characterization and generates image contrast as quantified by the apparent diffusion coefficient (ADC). This quantitative biomarker has been shown to be useful in discriminating between benign and malignant lesions as well as identifying some histopathological features.12,13 It has been suggested that areas exhibiting a low ADC value reflect dense cellular structures. A recent study suggests that restricted diffusion in rectal cancer as revealed at DW MRI is associated with an aggressive tumour profile.14 Based on these considerations, it was hypothesized that the pretreatment tumour ADC value may predict treatment response and local recurrence. In the study, this hypothesis was tested by retrospective evaluation of tumour ADC in patients with locally advanced rectal cancer who underwent neoadjuvant therapy prior to surgical resection.
Materials and methods Study cohort Institutional Review Board approval was obtained for this retrospective single centre study that was undertaken in compliance with the Health Insurance Portability and Accountability Act. Because the study was retrospective, the requirement for informed consent was waived. Patients who were treated for locally advanced rectal cancer (T2N2, T3, or T4 rectal adenocarcinoma, based upon pretreatment MRI between 2007 and 2011 at Massachusetts General Hospital, were evaluated. Inclusion criteria consisted of biopsy-proven cancer, locally advanced disease, neoadjuvant chemotherapy followed by surgery, and availability of pre-treatment DW-MRI images. Patients with
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remote metastases or unresectable primary tumours were excluded. Patients for whom the presence or absence of tumour recurrence was undetermined were also excluded. Patients with mucinous adenocarcinoma were also excluded due to distinctive MRI characteristics.15
MRI Imaging was performed on 1.5 T (General Electric, Milwaukee or Siemens, Erlangen, Germany) MRI machines using a phased-array body coil. Fat-saturated T1-weighted axial and coronal scans were performed [951 ms/12 ms repetition time (TR)/echo time (TE); 4 mm section thickness; 12 flip angle] before and after a bolus of 0.1 mmol/kg gadolinium (MagnevistÒ; Schering AG, Germany). T2weighted fast spin-echo sequences in sagittal, coronal, and transverse orientations were also obtained (5000 ms/ 96 ms TR/TE; 320 mm field of view; 3 mm section thickness; 120 flip angle). T2-TSE images were acquired in the axial plane (2000 ms/124 ms TR/TE; 1 mm section thickness; 110 flip angle). Axial DW-MRI images were obtained by using a DW-MRI echo-planar sequence (2800 ms/3200 ms TR/TE; 400 mm field of view; 128 128 matrix size; 4e6 mm section thickness; three signals acquired; 1.8 mm intersection gap; 1736 bandwidth) with an acquisition time of 23 s. The axial T2-weighted and DW-MRI sequences were angled in identical planes. ADC maps in grey-scale were automatically generated by the operating system using a mono-exponential decay model with b-values of 100 and 600 for the GE scanner and 50, 400, and 800 for the Siemens scanner using the formula S ¼ S0 e ADC (b). The MRI images were independently reviewed on a picture archiving and communication system (PACS; Agfa-Gevaert, Mortsel, Belgium) by two radiologists (S.S.H. and D.C.) each with >5 years of experience in interpreting abdominal MRI images. They were blinded to the patients’ initial MRI report, clinical history, response to the therapy, and presence or absence of recurrence. For ADC measurement, multiple, nonoverlapping regions of interest (ROIs) were drawn manually on a single section of the ADC map, matching the corresponding axial DW images, and the results were averaged. The primary intention was to cover the entire tumour area on a single section containing the largest available tumour area.16 The suitable section for measurement of ADC was selected after excluding areas of necrosis and degeneration. Multiple ROIs were drawn on the area corresponding to the tumour on the section irrespective of appearance of signal intensity on the ADC map. For the present study, the ADC maps used were generated with a bvalue of 600 for the GE machines and a b-value of 800 for the Siemens machine. The ROI had the mean area of 21 mm2 (range 15e25 mm2).
Treatment Patients received a fractioned dose of either 45 or 50.4 Gy over a mean period of 6 weeks. In addition, patients received chemotherapy agents consisting of FOLFOX [FOL, folinic acid (leucovorin); F, fluorouracil (5-FU); OX, oxaliplatin (Eloxatin)],
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5FU, or capecitabine. Patients underwent total mesorectal excision 4e10 weeks after completion of NACR.
Follow-up All outcomes were examined until 30 June 2012. Clinical, radiological, and pathological prognostic factors were derived from the patients’ records including age, plasma carcinoembryonic antigen (CEA) level, tumour size, clinical pretreatment stage (cT and cN) based on MRI findings, and tumour differentiation grade. Histopathologic evaluation of the surgical specimen was considered as the reference standard for treatment response. The resected tissue was evaluated using a standard pathology technique. The pathology report made note of the presence of residual tumour, grade, vessel invasion, and surgical margins. Responders were identified as having either the absence of residual cancer in the surgical specimen (pT0N0, complete responders) or presence of downstaging as compared to the pretreatment clinical MRI stage (partial responders). Patients who did not respond or progressed during treatment were considered non-responders.17 During the follow-up period absence or presence of recurrence was confirmed with pathology or follow-up computed tomography (CT) and/or MRI.
Statistical analysis Statistical software (SPSS, version 17.0) was used for analysis. An independent-sample t-test was used to compare mean ADC value between responders and nonresponders as well as between patients with and without recurrence. Receiver operator characteristics (ROC)-curve analyses were performed to evaluate the diagnostic performance of the ADC value of each reader for identification of (1) complete response and (2) recurrence using a nonparametric approach. Diagnostic accuracy of ADC for predicting response and recurrence was assessed using the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The area under the ROC curve (AUC) for predicting treatment response and tumoural recurrence was obtained for predictive variables (cT staging, baseline CEA, lymph node involvement, tumour grade, vascular invasion, surgical margin, and ADC value). Univariate and multivariate Cox proportional hazard analyses were performed for age, tumour size, cT staging, baseline CEA, lymph node involvement, tumour grade, vascular invasion, surgical margin, and tumour ADC value to determine their relationship with disease recurrence. Correlation between pretreatment ADC value and CEA level was investigated using Pearson correlation coefficient. To evaluate agreement between the two readers for measuring ADC values, a weighted kappa value with quadratic kappa weighting (0e0.2 poor, 0.21e0.4 fair, 0.41e0.6 moderate, 0.61e0.8 good and 0.81e1 excellent agreement) was obtained.18 For BlandeAltman analysis, the difference in the ADC values was compared with the averaged ADC values. The intraclass correlation coefficient was calculated as a measure of the precision of parameter estimates.
Results Patient population and treatment characteristics Forty-nine patients with a mean age of 54.8 years were included (31 men, 18 women). Most tumours were cT3 on pretreatment MRI images and 43 had positive nodal disease. Twenty-four patients received FOLFOX, 21 5-FU, and four capecitabine. Twenty-seven patients underwent low anterior resection, 16 had abdominoperineal resection, four had more extended surgery, and two had local excision. Resection was carried out at a median of 7 weeks after completion of NACR. The median time interval between the initial MRI and surgery was 112 (range 45e180) days.
Diagnostic performance for selection of responders Analysis of the surgical specimens demonstrated that seven patients had poorly differentiated, four poorly to moderately differentiated, 30 moderately differentiated, one moderately to well-differentiated, and seven welldifferentiated adenocarcinomas. Nodal disease was reported in 21 patients at pathology. Seven patients showed complete response whereas 42 had residual tumour. Overall, 20 patients were considered responders and 29 were non-responders. Pretreatment MRI findings of cT4 staging and lymph-node involvement, but not initial CEA levels and surgical tumour grade, were significantly related to poor treatment response. The mean pretreatment ADC value in responders was higher than the value in non-responders; however, this was only marginally significant (p ¼ 0.035, Table 1). The sensitivity, specificity, PPV, and NPV of the pretreatment ADC values of 0.833 103 mm2/s for Table 1 Prognostic factors in the responders group (n ¼ 20) and non-responders group (n ¼ 29). Variables
Responders
Lymph-node involvement (%) Y 95.8 N 4.2 cT staging (%) cT2 or cT3 79.2 cT4 20.8 Baseline CEA level (ng/ml) 5.22 Tumour grade (%) Poor 8.3 Pooremoderate 8.3 Moderate 62.5 Moderateegood 4.2 Good 16.7 Vascular invasion (%) Y 44 N 56 Surgical margin (%) Positive 33.3 Negative 62.5 Tumour ADC value Reader 1 1.028 103 Reader 2 0.911 103
Non-responders
p-Value
82.8 17.2
0.041
89.6 10.4 8.38
0.034 0.083
17.2 10.3 55.2 0 17.2
0.539
46.7 53.3
0.103
47.1 52.9
0.292
0.870 103 0.802 103
0.035
cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
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Figure 1 A 49-year-old man with adenocarcinoma of the rectum before chemoradiation. (a) Sagittal T2-weighted fast spin-echo MRI images show a T3 low rectal mass seen as circumferentially thickened rectum (arrowhead). (bec) Axial DW images show a bright focus of restricted diffusion in the tumour, with a corresponding axial ADC map (b ¼ 600, mean ADC ¼ 1.202 103 mm2/s). Pathological examination of the surgical specimen revealed complete response. No recurrence was reported during the follow-up.
prediction of treatment response was 75, 48, 76, and 48% for reader 1 and 65, 52, 75, and 40% for reader 2, respectively.
Diagnostic performance for predicting tumour recurrence Patients were followed for a mean of 16.4 months (range 6.3e60 months) after surgery. Absence or presence of recurrence was evaluated with biopsy in 23 patients and using follow-up MRI or CT in 26 patients. During this time, 17 patients (34.7%) showed local recurrence. The mean time from surgery to recurrence was 17.6 months. The mean ADC value was significantly lower in patients with tumour recurrence when compared to patients with no evidence of recurrence during follow-up (p < 0.001). Conversely, age, tumour size, cT staging, lymph-node involvement, presence of vascular invasion, positive surgical margins, and baseline CEA level showed no significant association. Among factors available before treatment, the multivariate analysis showed only tumour ADC to be a significant prognostic indicator for recurrence (reader 1: p ¼ 0.017, reader 2: p ¼ 0.018; Figs 1e3). These results are summarized in
Table 2. Tumour ADC had better performance than clinical staging, tumour grade, lymph node involvement, and CEA levels for predicting recurrence. AUC results for each variable are shown in Table 3. The overall diagnostic performance was higher for predicting recurrence when compared to selection of responders. The sensitivity, specificity, PPV, and NPV of the pretreatment ADC value of 0.833 103 mm2/s for prediction of recurrence was 86, 77, 67, and 91.1% for reader 1 and 80.1, 69, 58.2, and 86.5% for reader 2, respectively. ROC curves for predicting recurrence and the selection of responders are displayed in Fig 4.
Association between ADC and other prognostic factors Table 4 demonstrates the differences in pretreatment ADC values between the different subgroups of prognostic factors. There was no significant difference in mean ADCs in different subgroups of cT stage, lymph-node status, initial CEA level, surgical margins, vascular invasion, and tumour grade. However, a significant correlation (reader 1: r ¼ 0.360;
Figure 2 A 72-year-old woman with adenocarcinoma of the rectum before chemoradiation. (a) Sagittal T2-weighted fast spin-echo MRI images show diffuse infiltration of the rectal wall (T3 disease; arrowhead). (b) Axial DW images show high signal within the tumour (arrowhead) consistent with restricted diffusion. A corresponding ADC map is shown in (c). (b ¼ 800, mean ADC ¼ 0.726 103 mm2/s). Pathological examination of the resection specimen revealed residual tumour (partial responder). Local recurrence was reported after 8.1 months.
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Figure 3 A 57-year-old man with adenocarcinoma of the rectum before chemoradiation. (a) Sagittal T2-weighted fast spin-echo MRI images show diffuse infiltration of the rectal wall (T3 disease; arrowhead). (bec) Axial DW images show foci of restricted diffusion in the tumour (arrowhead) with a corresponding ADC map (b ¼ 800, mean ADC ¼ 0.595 103 mm2/s). Pathological examination of the surgical specimen revealed no response to therapy (non-responder). Local recurrence was reported after 4.7 months.
p ¼ 0.01; reader 2: r ¼ 0.415; p ¼ 0.006) was found between ADC values and CEA levels at final follow-up.
Interobserver agreement The interobserver agreement was good with a kappa value of 0.70. Graphic illustration with BlandeAltman plots is shown in Fig 5 demonstrating good measurement of reproducibility. The intraclass correlation coefficient was 0.88.
Discussion This report represents a comprehensive evaluation of pretreatment DW-MRI and clinical parameters as prognostic factors for predicting response to NACR as well as local recurrence. In the present retrospective study, both univariate and multivariate analyses identified pretreatment tumour ADC as an independent predictor of tumoural recurrence after NACR. Conversely, the pretreatment mean ADC value was higher in patients with response to NACR. The findings of the present study complement those of a recent study showing that tumour ADC values may predict the behaviour of rectal cancer.14 Table 2 Univariate and multivariate analysis for predictive variables in recurrence. Variable
Age Tumour size Lymph-node involvement cT staging Baseline CEA level Tumour grade Vascular invasion Surgical margin Tumour ADC value Reader 1 Reader 2
Univariate analysis
Multivariate analysis
HR
p-Value
HR
p-Value
0.977 1.05 1.98
0.180 0.416 0.353
0.994 1.17 1.02
0.780 0.086 0.420
0.905 1.001 0.472 1.04 1.07
0.840 0.965 0.362 0.370 0.110
1.30 1.070 1.015 1.754 0.994
0.329 0.460 0.492 0.788 0.284
0.071 0.077
0.001 0.001
0.099 0.099
0.001 0.008
HR, hazard ratio; cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
With the advent of new preoperative therapeutic strategies, identification of an individual’s tumour profile would enable determination of the risk of incomplete response to initial therapy leading to optimization of treatment strategies. Traditionally, evaluation of tumour size using CT and MRI were used to monitor tumour response to NACR, although often with a low correlation to the pathological findings. Functional imaging is increasingly used for assessment of treatment response and disease-free survival in various malignancies. DW-MRI has been used for treatment response evaluation at different time courses during chemoradiation.19e21 However, for rectal cancer there is no consensus as yet on the true clinical value of ADC measurements for predicting therapeutic response.22 Lambregts et al.21 demonstrated an improved diagnostic performance of MRI after the addition of DW imaging to standard MRI for selection of complete responders. In a recent study significant increases in tumour ADC were reported during NACR in the responders.23 Conversely, Sun et al.20 proposed that low pretherapy ADC in rectal carcinoma correlates with good response to NACR (ADC of 1.07 0.13 103 mm2/s versus 1.19 0.15 103 mm2/s). However, the results of the present study showed marginally higher ADC values in Table 3 Area under the curve (AUC) results for predicting treatment response and tumoural recurrence. Variables
Lymph-node involvement cT staging Baseline CEA level Tumour grade Vascular invasion Surgical margin Tumour ADC value Reader 1 Reader 2
Treatment response
Recurrence
AUC
95% CI
AUC
95% CI
0.443
0.270e0.616
0.605
0.396e0.814
0.431 0.581 0.509 0.608 0.421
0.255e0.607 0.391e0.771 0.334e0.683 0.435e0.780 0.244e0.599
0.564 0.530 0.420 0.709 0.519
0.374e0.754 0.309e0.751 0.209e0.632 0.520e0.899 0.308e0.729
0.676 0.634
0.521e0.831 0.474e0.793
0.856 0.791
0.753e0.956 0.658e0.924
CI, confidence interval; cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
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Figure 4 ROC curve for the ADC in predicting treatment response (aeb) and recurrence (ced) with different b-values.
responders. Considering the poor diagnostic performance of DW-MRI for predicting treatment response after NACR with the AUC ranging from 0.634e0.676, larger prospective studies are needed to validate the role of ADC in predicting response. Apart from predicting initial response to therapy, it is vital that the preoperative staging system distinguishes patients at high risk of disease progression after curative surgery. Currently, pathological evaluation of the surgical specimen is the only reliable surrogate marker that correlates to long-term oncological outcomes. However, such data are available only after completion of NACR and cannot be used as guidance for adjusting the therapeutic approach. Accordingly, development of non-invasive biomarkers with the potential to provide early prediction is essential. Such biomarkers would aid
in identifying patients with probable excellent long-term prognosis from those with adverse tumour biology who are at a high risk of recurrence. The latter group of patients may benefit from systemic treatment intensification, if identified early in the course of treatment, and as candidates for intensive follow-up regimes. The MERCURY study group reported good agreement between pathological results and T staging evaluation on MRI, and concluded that patients with more than 5 mm of extramural spread and those with T4 disease should be identified due to their markedly worse prognosis.24 A recent study assessed the value of DW-MRI as a potential marker of tumour aggressiveness in rectal cancer by analysing the relationship between tumoural ADC and histological prognostic parameters. They demonstrated significant differences in pretreatment ADC values based on mesorectal fascia
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Table 4 Correlations between pretreatment ADC values (103 mm2/s) and prognostic factors.
Lymph-node involvement cT staging Baseline CEA level (ng/ml) Tumour grade
Surgical margin Vascular invasion
Groups
No. of patients
Mean ADC (reader 1)
cN0 cNþ cT2e3 cT4 <5 5 Well Wellemoderate Moderate Moderateepoor Poor Y N Y N
6 43 41 8 25 14 7 1 30 4 7 5 44 18 31
0.933 0.945 0.932 0.951 0.915 0.896 0.938 0.721 0.948 1.070 0.828 0.925 0.917 0.867 0.802
0.033 0.190 0.042 0.048 0.047 0.064 0.092 0.0 0.049 0.107 0.084 0.103 0.060 0.046 0.35
Mean ADC (reader 2) 0.894 0.749 0.856 0.909 0.866 0.845 0.891 0.840 1.094 0.840 0.954 0.873 0.917 0.926 0.853
0.028 0.055 0.031 0.69 0.040 0.067 0.073 0.052 0.103 0.095 0.065 0.034 0.061 0.044 0.035
p-Value >0.05 >0.05 >0.05 >0.05
>0.05 >0.05
cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
invasion, lymph node status, and histological differentiation grades. They concluded that lower ADC values were associated with a more aggressive tumour profile.14 The findings of the present study concur with this report. To the authors’ knowledge, a correlation between pretreatment ADC values and disease progression in rectal cancer has not been the focus of previous studies. Lower ADC values were evident in patients with recurrence. Multivariate analysis identified tumour ADC as the only independently pretreatment prognostic indicator for recurrence. There was no relationship between age, tumour size, or tumour grade with recurrence. Recurrence was reported only in one patient with surgical margin involvement. Interestingly, there was a significant negative correlation between CEA biomarker levels at final follow-up and pretreatment ADC values in the present cohort of patients. This may provide further evidence for the predictive value of DW images for disease recurrence in rectal cancer, suggesting that ADC by itself correlates with disease behaviour and prognosis. As the ADC value in DW-MRI images indirectly measures cellularity, tumoural ADC may reflect the aggressiveness of the tumour tissue profile and
Figure 5 BlandeAltman plots of ADC values showing good measurement reproducibility.
predict patient outcome. This concept has been explored in animal studies of gastrointestinal cancers, human prostate cancer, and astrocytoma, all of which demonstrated an association between low ADC value and tumour grade and metastatic activity.25 There is no agreement regarding the role of ADC values as predictive factors in rectal cancer. The available literature has conflicting results. One major drawback could be the fact that in most studies evaluation was only performed by a single reader, which may contribute to the large variety in reported ADC results. In the present study, performance of two observers for classification of patients in terms of treatment response and long-term outcome was evaluated. The goal was to assess interobserver agreement for evaluating ADC values. The present results indicated a good agreement of the two readers. DW-MRI is thus beneficial by enhancing the confidence level of the readers. Nevertheless, interpretation errors were still observed resulting in a suboptimal specificity of 69e77%. In the ROC analysis of the prognostic factors in the present study, the AUCs of ADC values were higher than those of other variables for both predicting treatment response and recurrence. Using a cut-off value of 0.833 103 mm2/s for tumour ADC, excellent sensitivity was obtained but only moderate specificity. The use of DW-MRI as a standalone sequence is likely not sufficient and complimentary anatomical data would be useful in improving the specificity. The high NPV of ADC for predicting recurrence in the present cohort of patients could potentially enable pretreatment identification of patients with good long-term outcome. 5-FU-based chemoradiotherapy is regarded as the foundation of NACR in locally advanced rectal cancer. The present patients received three different NACR regimens and this may affect the results; however, majority of the cohort received 5-FU-based chemoradiotherapy (91.8%) and only 8.2% received capecitabine. A recent study investigated the efficacy of capecitabine in comparison with 5-FU-based chemoradiotherapy agents and demonstrated a similar local recurrence rate.26 Several limitations of this study should be noted. Biases could be present in the study population as this was a
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retrospective study using two different MRI machines and the sample size was small. Additionally, ADC values were measured on a single section containing the largest available tumour using multiple ROIs. Such averaging of ADCs may underestimate the biological significance of ADC in a heterogeneous tumour with variable cellularity. Although, this approach was selected to evaluate the diagnostic performance of an imaging marker that could be readily translatable to clinical daily work, the possible higher performance of outlining the whole tumour volume should not be ignored. The lack of standardization by a phantom study is another limitation of the present study. However, there is currently no suitable phantom that enables implementation of ADC assessments. The identification of tumour downstaging was based on a comparison between initial MRI T staging and pathological staging, which could have induced an inadvertent bias, as MRI has an inherent limitation and may underestimate or overestimate the tumour. In addition, disease involvement of the potential circumferential margin, which has been shown as a poor prognostic factor, was not taken into consideration in the present study because of the small size of the patient group. One may argue that the follow-up period was relatively short; however, it should be noted that a population-based study has demonstrated that the majority of patients with rectal cancer have local recurrence within 2 years after the primary surgery.6 Nevertheless, long-term follow-up is necessary to analyse overall survival. Despite these limitations, the present results seem to be a promising significant step towards the application of DW imaging as a predictive biomarker in patients who are candidates for NACR. Of course, these observations have to be considered preliminary, and the full prognostic significance of ADC should be investigated in prospective studies with longer follow-up periods. In conclusion, pretreatment rectal tumour ADC values may be an early predictor of treatment response and local recurrence in patients who undergo NACR followed by surgical resection. The authors suggest that DW-MRI could be a useful adjunct to include as part of a standard MRI protocol for imaging rectal cancer patients. This is a quantitative tool, which might play an important role in risk stratification for rectal cancer prior to initial treatment. Larger studies are needed to prospectively validate the utility of ADC as a noninvasive imaging biomarker in rectal cancer.
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The authors thank Dr Hui Zheng for assistance with statistical analysis of the data.
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II multicenter study with 3 years’ follow-up. J Clin Oncol 2004;22: 3016e22. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg 2012;99: 918e28. Heriot AG, Tekkis PP, Darzi A, et al. Surgery for local recurrence of rectal cancer. Colorectal Dis 2006;8:733e47. Palmer G, Martling A, Cedermark B, et al. A population-based study on the management and outcome in patients with locally recurrent rectal cancer. Ann Surg Oncol 2007;14:447e54. Stipa F, Giaccaglia V, Burza A. Management and outcome of local recurrence following transanal endoscopic microsurgery for rectal cancer. Dis Colon Rectum 2012;55:262e9. Barrett MW. Chemoradiation for rectal cancer: current methods. Semin Surg Oncol 1998;15:114e9. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001;358:1291e304. Jass JR, Love SB. Prognostic value of direct spread in Dukes’ C cases of rectal cancer. Dis Colon Rectum 1989;32:477e80. Willett CG, Badizadegan K, Ancukiewicz M, et al. Prognostic factors in stage T3N0 rectal cancer: do all patients require postoperative pelvic irradiation and chemotherapy? Dis Colon Rectum 1999;42:167e73. Schnapauff D, Zeile M, Niederhagen MB, et al. Diffusion-weighted echoplanar magnetic resonance imaging for the assessment of tumor cellularity in patients with soft-tissue sarcomas. J Magn Reson Imaging 2009;29:1355e9. Koh DM, Collins DJ. Diffusion-weighted MRI in the body: applications and challenges in oncology. AJR Am J Roentgenol 2007;188:1622e35. Curvo-Semedo L, Lambregts DM, Maas M, et al. Diffusion-weighted MRI in rectal cancer: apparent diffusion coefficient as a potential noninvasive marker of tumor aggressiveness. J Magn Reson Imaging 2012;35: 1365e71. Hussain SM, Outwater EK, Siegelman ES. Mucinous versus nonmucinous rectal carcinomas: differentiation with MR imaging. Radiology 1999;213:79e85. Lambregts DM, Beets GL, Maas M, et al. Tumour ADC measurements in rectal cancer: effect of ROI methods on ADC values and interobserver variability. Eur Radiol 2011;21:2567e74. Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012; 30:1770e6. Cohen J. Weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit. Psychol Bull 1968;70:213e20. Dzik-Jurasz A, Domenig C, George M, et al. Diffusion MRI for prediction of response of rectal cancer to chemoradiation. Lancet 2002;360:307e8. Sun YS, Zhang XP, Tang L, et al. Locally advanced rectal carcinoma treated with preoperative chemotherapy and radiation therapy: preliminary analysis of diffusion-weighted MR imaging for early detection of tumor histopathologic downstaging. Radiology 2009;254:170e8. Lambregts DM, Vandecaveye V, Barbaro B, et al. Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study. Ann Surg Oncol 2011;18: 2224e31. Patterson DM, Padhani AR, Collins DJ. Technology insight: water diffusion MRIda potential new biomarker of response to cancer therapy. Nat Clin Pract Oncol 2008;5:220e33. Barbaro B, Vitale R, Valentini V, et al. Diffusion-weighted magnetic resonance imaging in monitoring rectal cancer response to neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2011;83:594e9. MERCURY Study Group. Extramural depth of tumor invasion at thinsection MR in patients with rectal cancer: results of the MERCURY study. Radiology 2007;243:132e9. Tamada T, Sone T, Jo Y, et al. Apparent diffusion coefficient values in peripheral and transition zones of the prostate: comparison between normal and malignant prostatic tissues and correlation with histologic grade. J Magn Reson Imaging 2008;28:720e6. Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012;13:579e88.
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Apparent diffusion coefficient as a non-invasive predictor of treatment response and recurrence in locally advanced rectal cancer A. Elmi*, S.S. Hedgire, D. Covarrubias, S.M. Abtahi, P.F. Hahn, M. Harisinghani Division of Abdominal Imaging and Interventional Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
article in formation Article history: Received 29 January 2013 Received in revised form 8 May 2013 Accepted 15 May 2013
AIM: To evaluate the role of pretreatment apparent diffusion coefficient (ADC) as a predictor of treatment response and local recurrence in patients with locally advanced rectal cancer who underwent neoadjuvant therapy. MATERIALS AND METHODS: Forty-nine patients who underwent preoperative diffusionweighted magnetic resonance imaging (MRI) followed by neoadjuvant chemoradiation and surgery were enrolled in the study. The mean tumour ADC was measured independently from multiple, non-overlapping regions of interest (ROIs) to cover the entire tumour area on a single section by two radiologists and patients were followed postoperatively for a median of 16.4 months. Diagnostic accuracy of ADC for predicting treatment response and recurrence was evaluated using the area under the receiver-operating characteristic (ROC) curve, sensitivity, specificity, and predictive values. Univariate and multivariate analyses including clinical tumour (cT) staging, carcinoembryonic antigen (CEA) level, lymph-node involvement, tumour grade, surgical margin, vascular involvement, and ADC were performed with respect to recurrence. Interobserver agreement of ADC values was assessed. RESULTS: Twenty patients showed response to neoadjuvant therapy and recurrence was noted in 17 patients. Low pretreatment ADC, MRI findings of cT4 staging, and node involvement were significantly related to poor treatment response. Sensitivity and specificity of ADC ¼ 0.833 103 mm2/s for prediction of treatment response was 75 and 48% for reader 1 and 65 and 52% for reader 2, respectively. Univariate and multivariate analyses identified pretreatment tumour ADC as the only predictive factor for recurrence. Sensitivity and specificity of ADC ¼ 0.833 103 mm2/s for prediction of recurrence was 86 and 77% for reader 1 and 80 and 69% for reader 2, respectively. Interobserver agreement for measuring ADC was good with a kappa value of 0.70. CONCLUSION: Pretreatment rectal tumour ADC values may be an early biomarker for predicting treatment response and local recurrence in patients who underwent neoadjuvant chemoradiation. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction * Guarantor and correspondent: A. Elmi, Massachusetts General Hospital, Division of Abdominal Imaging and Interventional Radiology, 55 Fruit St, White 270, Boston, MA 02114, USA. Tel.: þ1 617 726 8380. E-mail address: [email protected] (A. Elmi).
Neoadjuvant chemoradiotherapy (NACR) followed by surgery has been established as the standard-of-care for locally advanced rectal cancer.1 There is significant individual variation in the response to NACR.2,3 Patients who
0009-9260/$ e see front matter Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2013.05.094
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achieve a pathological complete response have shown increased disease-free survival.4 Moreover, local recurrence after surgery remains a significant problem in patients with rectal cancer with reported incidence of 30e50%.5,6 Early detection is one of the cornerstones of successful management of local recurrence in rectal cancer; however, in the early phase, recurring tumour is often obscured on imaging by concomitant inflammation and scarring caused by chemoradiation and surgery.7 Therefore, it is important to identify prognostic factors in order to decide whether or not NACR is a favourable treatment modality and ideally to identify patients at high risk of disease recurrence who may benefit from intense neoadjuvant treatment protocols.8,9 Various preoperative and postoperative variables have been used to predict the degree of treatment response and recurrence after NACR but with questionable accuracy.10,11 The inclusion of biomarkers and/or imaging tools that mirror the behaviour of rectal cancer may potentially improve such predictive accuracy. Few studies have evaluated magnetic resonance imaging (MRI) for predicting the response to NACR in rectal cancer. Recently, anatomical MRI along with diffusion-weighted (DW) MRI has emerged as preoperative staging methods for rectal tumours. DW MRI, a component of functional MRI, is able to assess biological characteristics such as tissue cellularity and water content. This provides tissue characterization and generates image contrast as quantified by the apparent diffusion coefficient (ADC). This quantitative biomarker has been shown to be useful in discriminating between benign and malignant lesions as well as identifying some histopathological features.12,13 It has been suggested that areas exhibiting a low ADC value reflect dense cellular structures. A recent study suggests that restricted diffusion in rectal cancer as revealed at DW MRI is associated with an aggressive tumour profile.14 Based on these considerations, it was hypothesized that the pretreatment tumour ADC value may predict treatment response and local recurrence. In the study, this hypothesis was tested by retrospective evaluation of tumour ADC in patients with locally advanced rectal cancer who underwent neoadjuvant therapy prior to surgical resection.
Materials and methods Study cohort Institutional Review Board approval was obtained for this retrospective single centre study that was undertaken in compliance with the Health Insurance Portability and Accountability Act. Because the study was retrospective, the requirement for informed consent was waived. Patients who were treated for locally advanced rectal cancer (T2N2, T3, or T4 rectal adenocarcinoma, based upon pretreatment MRI between 2007 and 2011 at Massachusetts General Hospital, were evaluated. Inclusion criteria consisted of biopsy-proven cancer, locally advanced disease, neoadjuvant chemotherapy followed by surgery, and availability of pre-treatment DW-MRI images. Patients with
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remote metastases or unresectable primary tumours were excluded. Patients for whom the presence or absence of tumour recurrence was undetermined were also excluded. Patients with mucinous adenocarcinoma were also excluded due to distinctive MRI characteristics.15
MRI Imaging was performed on 1.5 T (General Electric, Milwaukee or Siemens, Erlangen, Germany) MRI machines using a phased-array body coil. Fat-saturated T1-weighted axial and coronal scans were performed [951 ms/12 ms repetition time (TR)/echo time (TE); 4 mm section thickness; 12 flip angle] before and after a bolus of 0.1 mmol/kg gadolinium (MagnevistÒ; Schering AG, Germany). T2weighted fast spin-echo sequences in sagittal, coronal, and transverse orientations were also obtained (5000 ms/ 96 ms TR/TE; 320 mm field of view; 3 mm section thickness; 120 flip angle). T2-TSE images were acquired in the axial plane (2000 ms/124 ms TR/TE; 1 mm section thickness; 110 flip angle). Axial DW-MRI images were obtained by using a DW-MRI echo-planar sequence (2800 ms/3200 ms TR/TE; 400 mm field of view; 128 128 matrix size; 4e6 mm section thickness; three signals acquired; 1.8 mm intersection gap; 1736 bandwidth) with an acquisition time of 23 s. The axial T2-weighted and DW-MRI sequences were angled in identical planes. ADC maps in grey-scale were automatically generated by the operating system using a mono-exponential decay model with b-values of 100 and 600 for the GE scanner and 50, 400, and 800 for the Siemens scanner using the formula S ¼ S0 e ADC (b). The MRI images were independently reviewed on a picture archiving and communication system (PACS; Agfa-Gevaert, Mortsel, Belgium) by two radiologists (S.S.H. and D.C.) each with >5 years of experience in interpreting abdominal MRI images. They were blinded to the patients’ initial MRI report, clinical history, response to the therapy, and presence or absence of recurrence. For ADC measurement, multiple, nonoverlapping regions of interest (ROIs) were drawn manually on a single section of the ADC map, matching the corresponding axial DW images, and the results were averaged. The primary intention was to cover the entire tumour area on a single section containing the largest available tumour area.16 The suitable section for measurement of ADC was selected after excluding areas of necrosis and degeneration. Multiple ROIs were drawn on the area corresponding to the tumour on the section irrespective of appearance of signal intensity on the ADC map. For the present study, the ADC maps used were generated with a bvalue of 600 for the GE machines and a b-value of 800 for the Siemens machine. The ROI had the mean area of 21 mm2 (range 15e25 mm2).
Treatment Patients received a fractioned dose of either 45 or 50.4 Gy over a mean period of 6 weeks. In addition, patients received chemotherapy agents consisting of FOLFOX [FOL, folinic acid (leucovorin); F, fluorouracil (5-FU); OX, oxaliplatin (Eloxatin)],
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5FU, or capecitabine. Patients underwent total mesorectal excision 4e10 weeks after completion of NACR.
Follow-up All outcomes were examined until 30 June 2012. Clinical, radiological, and pathological prognostic factors were derived from the patients’ records including age, plasma carcinoembryonic antigen (CEA) level, tumour size, clinical pretreatment stage (cT and cN) based on MRI findings, and tumour differentiation grade. Histopathologic evaluation of the surgical specimen was considered as the reference standard for treatment response. The resected tissue was evaluated using a standard pathology technique. The pathology report made note of the presence of residual tumour, grade, vessel invasion, and surgical margins. Responders were identified as having either the absence of residual cancer in the surgical specimen (pT0N0, complete responders) or presence of downstaging as compared to the pretreatment clinical MRI stage (partial responders). Patients who did not respond or progressed during treatment were considered non-responders.17 During the follow-up period absence or presence of recurrence was confirmed with pathology or follow-up computed tomography (CT) and/or MRI.
Statistical analysis Statistical software (SPSS, version 17.0) was used for analysis. An independent-sample t-test was used to compare mean ADC value between responders and nonresponders as well as between patients with and without recurrence. Receiver operator characteristics (ROC)-curve analyses were performed to evaluate the diagnostic performance of the ADC value of each reader for identification of (1) complete response and (2) recurrence using a nonparametric approach. Diagnostic accuracy of ADC for predicting response and recurrence was assessed using the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The area under the ROC curve (AUC) for predicting treatment response and tumoural recurrence was obtained for predictive variables (cT staging, baseline CEA, lymph node involvement, tumour grade, vascular invasion, surgical margin, and ADC value). Univariate and multivariate Cox proportional hazard analyses were performed for age, tumour size, cT staging, baseline CEA, lymph node involvement, tumour grade, vascular invasion, surgical margin, and tumour ADC value to determine their relationship with disease recurrence. Correlation between pretreatment ADC value and CEA level was investigated using Pearson correlation coefficient. To evaluate agreement between the two readers for measuring ADC values, a weighted kappa value with quadratic kappa weighting (0e0.2 poor, 0.21e0.4 fair, 0.41e0.6 moderate, 0.61e0.8 good and 0.81e1 excellent agreement) was obtained.18 For BlandeAltman analysis, the difference in the ADC values was compared with the averaged ADC values. The intraclass correlation coefficient was calculated as a measure of the precision of parameter estimates.
Results Patient population and treatment characteristics Forty-nine patients with a mean age of 54.8 years were included (31 men, 18 women). Most tumours were cT3 on pretreatment MRI images and 43 had positive nodal disease. Twenty-four patients received FOLFOX, 21 5-FU, and four capecitabine. Twenty-seven patients underwent low anterior resection, 16 had abdominoperineal resection, four had more extended surgery, and two had local excision. Resection was carried out at a median of 7 weeks after completion of NACR. The median time interval between the initial MRI and surgery was 112 (range 45e180) days.
Diagnostic performance for selection of responders Analysis of the surgical specimens demonstrated that seven patients had poorly differentiated, four poorly to moderately differentiated, 30 moderately differentiated, one moderately to well-differentiated, and seven welldifferentiated adenocarcinomas. Nodal disease was reported in 21 patients at pathology. Seven patients showed complete response whereas 42 had residual tumour. Overall, 20 patients were considered responders and 29 were non-responders. Pretreatment MRI findings of cT4 staging and lymph-node involvement, but not initial CEA levels and surgical tumour grade, were significantly related to poor treatment response. The mean pretreatment ADC value in responders was higher than the value in non-responders; however, this was only marginally significant (p ¼ 0.035, Table 1). The sensitivity, specificity, PPV, and NPV of the pretreatment ADC values of 0.833 103 mm2/s for Table 1 Prognostic factors in the responders group (n ¼ 20) and non-responders group (n ¼ 29). Variables
Responders
Lymph-node involvement (%) Y 95.8 N 4.2 cT staging (%) cT2 or cT3 79.2 cT4 20.8 Baseline CEA level (ng/ml) 5.22 Tumour grade (%) Poor 8.3 Pooremoderate 8.3 Moderate 62.5 Moderateegood 4.2 Good 16.7 Vascular invasion (%) Y 44 N 56 Surgical margin (%) Positive 33.3 Negative 62.5 Tumour ADC value Reader 1 1.028 103 Reader 2 0.911 103
Non-responders
p-Value
82.8 17.2
0.041
89.6 10.4 8.38
0.034 0.083
17.2 10.3 55.2 0 17.2
0.539
46.7 53.3
0.103
47.1 52.9
0.292
0.870 103 0.802 103
0.035
cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
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Figure 1 A 49-year-old man with adenocarcinoma of the rectum before chemoradiation. (a) Sagittal T2-weighted fast spin-echo MRI images show a T3 low rectal mass seen as circumferentially thickened rectum (arrowhead). (bec) Axial DW images show a bright focus of restricted diffusion in the tumour, with a corresponding axial ADC map (b ¼ 600, mean ADC ¼ 1.202 103 mm2/s). Pathological examination of the surgical specimen revealed complete response. No recurrence was reported during the follow-up.
prediction of treatment response was 75, 48, 76, and 48% for reader 1 and 65, 52, 75, and 40% for reader 2, respectively.
Diagnostic performance for predicting tumour recurrence Patients were followed for a mean of 16.4 months (range 6.3e60 months) after surgery. Absence or presence of recurrence was evaluated with biopsy in 23 patients and using follow-up MRI or CT in 26 patients. During this time, 17 patients (34.7%) showed local recurrence. The mean time from surgery to recurrence was 17.6 months. The mean ADC value was significantly lower in patients with tumour recurrence when compared to patients with no evidence of recurrence during follow-up (p < 0.001). Conversely, age, tumour size, cT staging, lymph-node involvement, presence of vascular invasion, positive surgical margins, and baseline CEA level showed no significant association. Among factors available before treatment, the multivariate analysis showed only tumour ADC to be a significant prognostic indicator for recurrence (reader 1: p ¼ 0.017, reader 2: p ¼ 0.018; Figs 1e3). These results are summarized in
Table 2. Tumour ADC had better performance than clinical staging, tumour grade, lymph node involvement, and CEA levels for predicting recurrence. AUC results for each variable are shown in Table 3. The overall diagnostic performance was higher for predicting recurrence when compared to selection of responders. The sensitivity, specificity, PPV, and NPV of the pretreatment ADC value of 0.833 103 mm2/s for prediction of recurrence was 86, 77, 67, and 91.1% for reader 1 and 80.1, 69, 58.2, and 86.5% for reader 2, respectively. ROC curves for predicting recurrence and the selection of responders are displayed in Fig 4.
Association between ADC and other prognostic factors Table 4 demonstrates the differences in pretreatment ADC values between the different subgroups of prognostic factors. There was no significant difference in mean ADCs in different subgroups of cT stage, lymph-node status, initial CEA level, surgical margins, vascular invasion, and tumour grade. However, a significant correlation (reader 1: r ¼ 0.360;
Figure 2 A 72-year-old woman with adenocarcinoma of the rectum before chemoradiation. (a) Sagittal T2-weighted fast spin-echo MRI images show diffuse infiltration of the rectal wall (T3 disease; arrowhead). (b) Axial DW images show high signal within the tumour (arrowhead) consistent with restricted diffusion. A corresponding ADC map is shown in (c). (b ¼ 800, mean ADC ¼ 0.726 103 mm2/s). Pathological examination of the resection specimen revealed residual tumour (partial responder). Local recurrence was reported after 8.1 months.
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Figure 3 A 57-year-old man with adenocarcinoma of the rectum before chemoradiation. (a) Sagittal T2-weighted fast spin-echo MRI images show diffuse infiltration of the rectal wall (T3 disease; arrowhead). (bec) Axial DW images show foci of restricted diffusion in the tumour (arrowhead) with a corresponding ADC map (b ¼ 800, mean ADC ¼ 0.595 103 mm2/s). Pathological examination of the surgical specimen revealed no response to therapy (non-responder). Local recurrence was reported after 4.7 months.
p ¼ 0.01; reader 2: r ¼ 0.415; p ¼ 0.006) was found between ADC values and CEA levels at final follow-up.
Interobserver agreement The interobserver agreement was good with a kappa value of 0.70. Graphic illustration with BlandeAltman plots is shown in Fig 5 demonstrating good measurement of reproducibility. The intraclass correlation coefficient was 0.88.
Discussion This report represents a comprehensive evaluation of pretreatment DW-MRI and clinical parameters as prognostic factors for predicting response to NACR as well as local recurrence. In the present retrospective study, both univariate and multivariate analyses identified pretreatment tumour ADC as an independent predictor of tumoural recurrence after NACR. Conversely, the pretreatment mean ADC value was higher in patients with response to NACR. The findings of the present study complement those of a recent study showing that tumour ADC values may predict the behaviour of rectal cancer.14 Table 2 Univariate and multivariate analysis for predictive variables in recurrence. Variable
Age Tumour size Lymph-node involvement cT staging Baseline CEA level Tumour grade Vascular invasion Surgical margin Tumour ADC value Reader 1 Reader 2
Univariate analysis
Multivariate analysis
HR
p-Value
HR
p-Value
0.977 1.05 1.98
0.180 0.416 0.353
0.994 1.17 1.02
0.780 0.086 0.420
0.905 1.001 0.472 1.04 1.07
0.840 0.965 0.362 0.370 0.110
1.30 1.070 1.015 1.754 0.994
0.329 0.460 0.492 0.788 0.284
0.071 0.077
0.001 0.001
0.099 0.099
0.001 0.008
HR, hazard ratio; cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
With the advent of new preoperative therapeutic strategies, identification of an individual’s tumour profile would enable determination of the risk of incomplete response to initial therapy leading to optimization of treatment strategies. Traditionally, evaluation of tumour size using CT and MRI were used to monitor tumour response to NACR, although often with a low correlation to the pathological findings. Functional imaging is increasingly used for assessment of treatment response and disease-free survival in various malignancies. DW-MRI has been used for treatment response evaluation at different time courses during chemoradiation.19e21 However, for rectal cancer there is no consensus as yet on the true clinical value of ADC measurements for predicting therapeutic response.22 Lambregts et al.21 demonstrated an improved diagnostic performance of MRI after the addition of DW imaging to standard MRI for selection of complete responders. In a recent study significant increases in tumour ADC were reported during NACR in the responders.23 Conversely, Sun et al.20 proposed that low pretherapy ADC in rectal carcinoma correlates with good response to NACR (ADC of 1.07 0.13 103 mm2/s versus 1.19 0.15 103 mm2/s). However, the results of the present study showed marginally higher ADC values in Table 3 Area under the curve (AUC) results for predicting treatment response and tumoural recurrence. Variables
Lymph-node involvement cT staging Baseline CEA level Tumour grade Vascular invasion Surgical margin Tumour ADC value Reader 1 Reader 2
Treatment response
Recurrence
AUC
95% CI
AUC
95% CI
0.443
0.270e0.616
0.605
0.396e0.814
0.431 0.581 0.509 0.608 0.421
0.255e0.607 0.391e0.771 0.334e0.683 0.435e0.780 0.244e0.599
0.564 0.530 0.420 0.709 0.519
0.374e0.754 0.309e0.751 0.209e0.632 0.520e0.899 0.308e0.729
0.676 0.634
0.521e0.831 0.474e0.793
0.856 0.791
0.753e0.956 0.658e0.924
CI, confidence interval; cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
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Figure 4 ROC curve for the ADC in predicting treatment response (aeb) and recurrence (ced) with different b-values.
responders. Considering the poor diagnostic performance of DW-MRI for predicting treatment response after NACR with the AUC ranging from 0.634e0.676, larger prospective studies are needed to validate the role of ADC in predicting response. Apart from predicting initial response to therapy, it is vital that the preoperative staging system distinguishes patients at high risk of disease progression after curative surgery. Currently, pathological evaluation of the surgical specimen is the only reliable surrogate marker that correlates to long-term oncological outcomes. However, such data are available only after completion of NACR and cannot be used as guidance for adjusting the therapeutic approach. Accordingly, development of non-invasive biomarkers with the potential to provide early prediction is essential. Such biomarkers would aid
in identifying patients with probable excellent long-term prognosis from those with adverse tumour biology who are at a high risk of recurrence. The latter group of patients may benefit from systemic treatment intensification, if identified early in the course of treatment, and as candidates for intensive follow-up regimes. The MERCURY study group reported good agreement between pathological results and T staging evaluation on MRI, and concluded that patients with more than 5 mm of extramural spread and those with T4 disease should be identified due to their markedly worse prognosis.24 A recent study assessed the value of DW-MRI as a potential marker of tumour aggressiveness in rectal cancer by analysing the relationship between tumoural ADC and histological prognostic parameters. They demonstrated significant differences in pretreatment ADC values based on mesorectal fascia
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Table 4 Correlations between pretreatment ADC values (103 mm2/s) and prognostic factors.
Lymph-node involvement cT staging Baseline CEA level (ng/ml) Tumour grade
Surgical margin Vascular invasion
Groups
No. of patients
Mean ADC (reader 1)
cN0 cNþ cT2e3 cT4 <5 5 Well Wellemoderate Moderate Moderateepoor Poor Y N Y N
6 43 41 8 25 14 7 1 30 4 7 5 44 18 31
0.933 0.945 0.932 0.951 0.915 0.896 0.938 0.721 0.948 1.070 0.828 0.925 0.917 0.867 0.802
0.033 0.190 0.042 0.048 0.047 0.064 0.092 0.0 0.049 0.107 0.084 0.103 0.060 0.046 0.35
Mean ADC (reader 2) 0.894 0.749 0.856 0.909 0.866 0.845 0.891 0.840 1.094 0.840 0.954 0.873 0.917 0.926 0.853
0.028 0.055 0.031 0.69 0.040 0.067 0.073 0.052 0.103 0.095 0.065 0.034 0.061 0.044 0.035
p-Value >0.05 >0.05 >0.05 >0.05
>0.05 >0.05
cT, clinical tumour; CEA, carcinoembryonic antigen; ADC, apparent diffusion coefficient.
invasion, lymph node status, and histological differentiation grades. They concluded that lower ADC values were associated with a more aggressive tumour profile.14 The findings of the present study concur with this report. To the authors’ knowledge, a correlation between pretreatment ADC values and disease progression in rectal cancer has not been the focus of previous studies. Lower ADC values were evident in patients with recurrence. Multivariate analysis identified tumour ADC as the only independently pretreatment prognostic indicator for recurrence. There was no relationship between age, tumour size, or tumour grade with recurrence. Recurrence was reported only in one patient with surgical margin involvement. Interestingly, there was a significant negative correlation between CEA biomarker levels at final follow-up and pretreatment ADC values in the present cohort of patients. This may provide further evidence for the predictive value of DW images for disease recurrence in rectal cancer, suggesting that ADC by itself correlates with disease behaviour and prognosis. As the ADC value in DW-MRI images indirectly measures cellularity, tumoural ADC may reflect the aggressiveness of the tumour tissue profile and
Figure 5 BlandeAltman plots of ADC values showing good measurement reproducibility.
predict patient outcome. This concept has been explored in animal studies of gastrointestinal cancers, human prostate cancer, and astrocytoma, all of which demonstrated an association between low ADC value and tumour grade and metastatic activity.25 There is no agreement regarding the role of ADC values as predictive factors in rectal cancer. The available literature has conflicting results. One major drawback could be the fact that in most studies evaluation was only performed by a single reader, which may contribute to the large variety in reported ADC results. In the present study, performance of two observers for classification of patients in terms of treatment response and long-term outcome was evaluated. The goal was to assess interobserver agreement for evaluating ADC values. The present results indicated a good agreement of the two readers. DW-MRI is thus beneficial by enhancing the confidence level of the readers. Nevertheless, interpretation errors were still observed resulting in a suboptimal specificity of 69e77%. In the ROC analysis of the prognostic factors in the present study, the AUCs of ADC values were higher than those of other variables for both predicting treatment response and recurrence. Using a cut-off value of 0.833 103 mm2/s for tumour ADC, excellent sensitivity was obtained but only moderate specificity. The use of DW-MRI as a standalone sequence is likely not sufficient and complimentary anatomical data would be useful in improving the specificity. The high NPV of ADC for predicting recurrence in the present cohort of patients could potentially enable pretreatment identification of patients with good long-term outcome. 5-FU-based chemoradiotherapy is regarded as the foundation of NACR in locally advanced rectal cancer. The present patients received three different NACR regimens and this may affect the results; however, majority of the cohort received 5-FU-based chemoradiotherapy (91.8%) and only 8.2% received capecitabine. A recent study investigated the efficacy of capecitabine in comparison with 5-FU-based chemoradiotherapy agents and demonstrated a similar local recurrence rate.26 Several limitations of this study should be noted. Biases could be present in the study population as this was a
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retrospective study using two different MRI machines and the sample size was small. Additionally, ADC values were measured on a single section containing the largest available tumour using multiple ROIs. Such averaging of ADCs may underestimate the biological significance of ADC in a heterogeneous tumour with variable cellularity. Although, this approach was selected to evaluate the diagnostic performance of an imaging marker that could be readily translatable to clinical daily work, the possible higher performance of outlining the whole tumour volume should not be ignored. The lack of standardization by a phantom study is another limitation of the present study. However, there is currently no suitable phantom that enables implementation of ADC assessments. The identification of tumour downstaging was based on a comparison between initial MRI T staging and pathological staging, which could have induced an inadvertent bias, as MRI has an inherent limitation and may underestimate or overestimate the tumour. In addition, disease involvement of the potential circumferential margin, which has been shown as a poor prognostic factor, was not taken into consideration in the present study because of the small size of the patient group. One may argue that the follow-up period was relatively short; however, it should be noted that a population-based study has demonstrated that the majority of patients with rectal cancer have local recurrence within 2 years after the primary surgery.6 Nevertheless, long-term follow-up is necessary to analyse overall survival. Despite these limitations, the present results seem to be a promising significant step towards the application of DW imaging as a predictive biomarker in patients who are candidates for NACR. Of course, these observations have to be considered preliminary, and the full prognostic significance of ADC should be investigated in prospective studies with longer follow-up periods. In conclusion, pretreatment rectal tumour ADC values may be an early predictor of treatment response and local recurrence in patients who undergo NACR followed by surgical resection. The authors suggest that DW-MRI could be a useful adjunct to include as part of a standard MRI protocol for imaging rectal cancer patients. This is a quantitative tool, which might play an important role in risk stratification for rectal cancer prior to initial treatment. Larger studies are needed to prospectively validate the utility of ADC as a noninvasive imaging biomarker in rectal cancer.
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Acknowledgements
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The authors thank Dr Hui Zheng for assistance with statistical analysis of the data.
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